PMID- 33681788
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220421
IS  - 2632-6140 (Electronic)
IS  - 2632-6140 (Linking)
VI  - 2
IP  - 1
DP  - 2020
TI  - Safety and acceptability of clozapine and risperidone in progressive multiple 
      sclerosis: a phase I, randomised, blinded, placebo-controlled trial.
PG  - e000060
LID - 10.1136/bmjno-2020-000060 [doi]
LID - e000060
AB  - OBJECTIVE: Because clozapine and risperidone have been shown to reduce 
      neuroinflammation in humans and mice, the Clozapine and Risperidone in 
      Progressive Multiple Sclerosis (CRISP) trial was conducted to determine whether 
      clozapine and risperidone are suitable for progressive multiple sclerosis (pMS). 
      METHODS: The CRISP trial (ACTRN12616000178448) was a blinded, randomised, 
      placebo-controlled trial with three parallel arms (n=12/arm). Participants with 
      pMS were randomised to clozapine (100-150 mg/day), risperidone (2.0-3.5 mg/day) 
      or placebo for 6 months. The primary outcome measures were safety (adverse events 
      (AEs)/serious adverse events (SAE)) and acceptability (Treatment Satisfaction 
      Questionnaire for Medication-9). RESULTS: An interim analysis (n=9) revealed 
      significant differences in the time-on-trial between treatment groups and placebo 
      (p=0.030 and 0.025, clozapine and risperidone, respectively) with all 
      participants receiving clozapine being withdrawn during the titration period 
      (mean dose=35+/-15 mg/day). Participants receiving clozapine or risperidone 
      reported a significantly higher rate of AEs than placebo (p=0.00001) but not 
      SAEs. Specifically, low doses of clozapine appeared to cause an acute and 
      dose-related intoxicant effect in patients with pMS who had fairly severe chronic 
      spastic ataxic gait and worsening over all mobility, which resolved on drug 
      cessation. INTERPRETATION: The CRISP trial results suggest that patients with pMS 
      may experience increased sensitivity to clozapine and risperidone and indicate 
      that the dose and/or titration schedule developed for schizophrenia may not be 
      suitable for pMS. While these findings do not negate the potential of these drugs 
      to reduce multiple sclerosis-associated neuroinflammation, they highlight the 
      need for further research to understand the pharmacodynamic profile and effect of 
      clozapine and risperidone in patients with pMS. TRIAL REGISTRATION NUMBER: 
      ACTRN12616000178448.
CI  - (c) Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - La Flamme, Anne C
AU  - La Flamme AC
AD  - School of Biological Sciences, Victoria University of Wellington, Wellington, New 
      Zealand.
AD  - Malaghan Institute of Medical Research, Wellington, New Zealand.
FAU - Abernethy, David
AU  - Abernethy D
AD  - Neurology, Wellington Regional Hospital, Wellington, New Zealand.
FAU - Sim, Dalice
AU  - Sim D
AD  - Biostatistical Consulting Group, University of Otago, Wellington, New Zealand.
FAU - Goode, Liz
AU  - Goode L
AD  - Neurology, Wellington Regional Hospital, Wellington, New Zealand.
FAU - Lockhart, Michelle
AU  - Lockhart M
AD  - Pharmaceuticol Ltd, Auckland, New Zealand.
FAU - Bourke, David
AU  - Bourke D
AD  - Neurology, Wellington Regional Hospital, Wellington, New Zealand.
FAU - Milner, Imogen
AU  - Milner I
AD  - Neurology, Wellington Regional Hospital, Wellington, New Zealand.
FAU - Garrill, Toni-Marie
AU  - Garrill TM
AD  - Neurology, Wellington Regional Hospital, Wellington, New Zealand.
FAU - Joshi, Purwa
AU  - Joshi P
AD  - Neurology, Wellington Regional Hospital, Wellington, New Zealand.
FAU - Watson, Eloise
AU  - Watson E
AD  - Neurology, Wellington Regional Hospital, Wellington, New Zealand.
FAU - Smyth, Duncan
AU  - Smyth D
AD  - Neurology, Wellington Regional Hospital, Wellington, New Zealand.
FAU - Lance, Sean
AU  - Lance S
AD  - Hutt Valley District Health Board, Lower Hutt, New Zealand.
FAU - Connor, Bronwen
AU  - Connor B
AD  - Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, 
      Faculty of Medical and Health Sciences, University of Auckland, Auckland, New 
      Zealand.
LA  - eng
PT  - Journal Article
DEP - 20200709
PL  - England
TA  - BMJ Neurol Open
JT  - BMJ neurology open
JID - 101775450
PMC - PMC7903182
OTO - NOTNLM
OT  - multiple sclerosis
COIS- Competing interests: ACL and BC have a patent for the use of clozapine and 
      risperidone during MS. ACL is a founding scientist and shareholder in ReKover 
      Therapeutics, which has no relationship to the Clozapine and Risperidone in 
      Progressive Multiple Sclerosis study. In addition, BC has a patent 
      PCT/US2011/042244 issued.
EDAT- 2021/03/09 06:00
MHDA- 2021/03/09 06:01
PMCR- 2020/07/09
CRDT- 2021/03/08 05:58
PHST- 2020/03/23 00:00 [received]
PHST- 2020/05/28 00:00 [revised]
PHST- 2020/06/01 00:00 [accepted]
PHST- 2021/03/08 05:58 [entrez]
PHST- 2021/03/09 06:00 [pubmed]
PHST- 2021/03/09 06:01 [medline]
PHST- 2020/07/09 00:00 [pmc-release]
AID - bmjno-2020-000060 [pii]
AID - 10.1136/bmjno-2020-000060 [doi]
PST - epublish
SO  - BMJ Neurol Open. 2020 Jul 9;2(1):e000060. doi: 10.1136/bmjno-2020-000060. 
      eCollection 2020.